Retinoid-related orphan receptor gamma (RORγ) is a nuclear receptor that binds to DNA and regulates transcription (NPL 1). Two isoforms of RORγ that differ only in the N-terminus are generated from the RORC gene; RORγ1 and RORγt (also referred to as RORγ2) (NPL 2). RORγ is used as a term to describe both isoforms of RORγ1 and RORγt.
RORγ1 is expressed in a variety of tissues including muscle, kidney, liver, and lung and is known to regulate adipogenesis (NPL 3). Loss of the RORC gene in mice accelerates preadipocyte differentiation to small adipocytes and protects against high fat diet induced insulin resistance. Consequently, by inhibiting the function of RORγ1, insulin resistance could be improved.
RORγt is expressed exclusively in cells of the immune system (NPLs 4 and 5) and is a master regulator of a Th17 cell-related transcriptional network associated with autoimmune pathology. Th17 cells are a subset of CD4+ helper T cells implicated as key drivers of the inflammatory process in autoimmunity and characterized by production of the pro-inflammatory cytokine IL-17A. Th17 cells also express CCR6, which mediates migration to sites of inflammation, are maintained and expanded by IL-23, through the IL-23 receptor (IL23R), and express other pro-inflammatory cytokines and chemokines, including IL-17F, IL-21, IL-22, CCL20 and GM-CSF, which together promote recruitment of other inflammatory cell types, especially neutrophils, to mediate pathology at the target tissue. RORγt is required for the differentiation of Th17 cells and directly and indirectly regulates expression of many of these pro-inflammatory mediators (NPL 6). RORγ-deficient mice have significantly reduced numbers of Th17 cells in vivo, lack the ability to produce IL-17A and other Th17-related cytokines ex vivo, and show resistance to induction of various disease models such as EAE, dermatitis, enteritis and nephritis (NPLs 6, and 12 to 14). Therefore, by inhibiting the function of RORγ, development of various autoimmune diseases and inflammatory diseases, in which the Th17 cell-related cytokines are involved, could be suppressed. Furthermore, expression of RORγt and the consequent expression of the Th17 cell-related transcriptional network has been observed in other immune cell types that may also be important in disease pathogenesis, namely CD8+ T cells, so called Tc17s, γδ T cells, natural killer T cells, innate lymphoid cells, natural killer cells, and mast cells (NPLs 7 and 8).
Th17 cell-related cytokines and chemokines have been implicated in the pathogenesis of various human autoimmune and inflammatory diseases including multiple sclerosis, rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, cystic fibrosis, asthma, chronic obstructive pulmonary disease, emphysema, lung fibrosis, systemic erythematodes, vasculitis, Wegener granuloma, polymyalgia rheumatica, giant cell arteritis, arteriosclerosis, autoimmune myositis, uveitis, dry eye, inflammatory bowel disease, alcohol-induced hepatitis, non-alcoholic steatohepatitis, primary biliary cirrhosis, viral hepatitis and type 1 diabetes. (NPLs 9 to 11).
RORγt is known to possess an inhibitory effect on the anti-tumorigenic activity of Th9 cells, a subtype of helper T cells (NPL 15). In the RORγ-deficient mice, production of IL-9 from Th9 cells is enhanced and tumor formation is delayed in mice injected with melanoma cells. Therefore, it is thought that, by inhibiting the function of RORγ, the function of Th9 cells is activated and formation of melanoma and other malignant tumors can be suppressed.
From the evidence described above, a RORγ modulator can be expected to show therapeutic or preventive benefit in treatment of; metabolic diseases such as diabetes; for autoimmune diseases or inflammatory diseases and; for melanoma and other cancer diseases.